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Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues

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Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues cells Review Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues 1,2, 1, 1, Jacob A. Herring y , Weston S. Elison y and Jeffery S. Tessem * 1 Nutrition, Dietetics and Food Science Department, Brigham Young University, Provo, UT 84602, USA; [email protected] (J.A.H.); [email protected] (W.S.E.) 2 Microbiology and Molecular Biology Department, Brigham Young University, Provo, UT 84602, USA * Correspondence: Jeff[email protected]; Tel.: +1-801-422-9082 These authors contributed equally to this work. y Received: 1 October 2019; Accepted: 30 October 2019; Published: 1 November 2019 Abstract: The Nr4a family of nuclear hormone receptors is composed of three members—Nr4a1/Nur77, Nr4a2/Nurr1 and Nr4a3/Nor1. While currently defined as ligandless, these transcription factors have been shown to regulate varied processes across a host of tissues. Of particular interest, the Nr4a family impinge, in a tissue dependent fashion, on cellular proliferation, apoptosis and fuel utilization. The regulation of these processes occurs through both nuclear and non-genomic pathways. The purpose of this review is to provide a balanced perspective of the tissue specific and Nr4a family member specific, effects on cellular proliferation, apoptosis and fuel utilization. Keywords: Nr4a1; Nr4a2; Nr4a3; nuclear hormone receptors; metabolism; fuel utilization; proliferation; apoptosis 1. Introduction The Nr4a family consists of three members, Nr4a1 (Nur77/TR3/NGFI-B), Nr4a2/Nurr1 (TINUR/NOT) and Nr4a3/NOR1 (MINOR/CSMF). The three members have a high degree of sequence homology, with each containing a ligand-independent activation function-1 domain, transactivation domain necessary for transcriptional activity and cofactor binding, a DNA binding domain and a ligand binding domain containing a ligand-dependent AF-2 transactivation domain [1–3]. While currently defined as orphaned receptors with no known endogenous ligand, recent reports suggest that the Nr4a family’s transcription factor function may be regulated through binding unsaturated fatty acids in the ligand binding domain [4–6]. The Nr4a family binds directly as monomers or homodimers to promoters of target genes that contain the NBRE (NGFIB Response Element-AAAGGTCA) motif [7]. The Nr4as can also form heterodimers and bind to the NuRE (Nur Response element-AAT(G/A)(C/T)CA) [8,9]. Finally, Nr4a1 and Nr4a2 have been shown to forms dimers with retinoid X receptors and bind to the DR5 elements [10,11]. While there is a high degree of similarity between the three family members, the different members have differing affinity for co-factors and response elements, thus giving specificity to each [12]. The Nr4a family is widely expressed across various tissues [13]. The family was first discovered in the nervous system [14–17]. Nr4a’s have been shown to be critical in the hematopoietic system [18], adipose tissue [19], liver [20], muscle [21] and β-cells [22], among other tissues [23,24]. In these tissues, the function of Nr4a family members fall into one of two categories. The majority of Nr4a activity is due to direct activation or repression of transcriptional target expression. Interestingly, a growing Cells 2019, 8, 1373; doi:10.3390/cells8111373 www.mdpi.com/journal/cells Cells 2019, 8, 1373 2 of 32 body of information is demonstrating a direct non-genomic role of Nr4a’s through interaction with binding partners [25]. While the Nr4a’s are associated with various cellular processes, three are of particular interest. The Nr4a’s, across various tissue types, impinge on cellular proliferation, apoptosis and fuel utilization. These pathways are intimately connected. The cells ability and choice of macronutrients as a fuel source and their ability to utilize these molecules, greatly affects proliferation and cell survival. The type of metabolic pathways and choice of fuel oxidation is tightly coordinated with a cells ability to proliferate. Similarly, defective fuel utilization pathways or lack of oxidizable macronutrients, can impinges on apoptosis. Finally, signals that induce cell proliferation and apoptosis are in direct opposition to each other. This review will focus on the genomic and non-genomic Nr4a targets that allow for modulation of proliferation, apoptosis and fuel utilization. 2. Proliferation The Nr4a subfamily is known to regulate cellular proliferation in a tissue dependent manner. Key genes shown to be regulated by Nr4a’s include cyclins, cyclin dependent kinases and other ancillary cell cycle genes. Due to this, Nr4a1, Nr4a2 and Nr4a3 are potential therapeutic targets in many cancers, however their specific roles vary between tissues and among tumors from the same organ. The genes that have been shown to be transcriptionally regulated by the Nr4a’s that are essential for cellular proliferation are summarized in Table1. Table 1. Genes regulated by the Nr4a’s that are associated with cellular proliferation, defined by tissue of interest. References are given for each gene. Tissue/Cell Line Nr4a1 Nr4a2 Nr4a3 Liver NF-κB[26]; STAT3 [26]; Cyclin B1 Primary Hepatocytes (Partial Cyclin D1 [27]; Cyclin E1 [27]; [26]; Cyclin d1 [26]; Cyclin E1 [26]; Hepatectomy) VCAM1 [27]; PCNA; [27] Cdk4 [26]; Cdk2 [26] ERK1/2 [28,29]; p38 Hepatic Stellate Cells [28,29]; JNK [28] Muscle STAT3 [30]; Pim-1 [30]; NFAT [30]; Cyclin D1 [35–37]; Cyclin D2 Primary Vascular Smooth Muscle Cyclin D1 [30,31]; PCNA [30,31]; p27Kip1 [34] [35]; PCNA [37]; p27Kip1 [32,33] ERK1/2 [38]; AKT [38]; Primary Ventricularmyocytes DUSP2 [38]; DUSP14 [38] B-cell Cyclin E1 [22]; E2F1 [22]; Cyclin E1 [22]; E2F1 [22]; Ube2c [22]; Ins-1 832/13 Cells Ube’2c [22]; Cdk5r1 [39]; Cdk5r1 [39]; p21Cip1 [22]; pRB [39] p21Cip1 [22]; pRB [39] Immune Primary T Cells Irf4 [40] Primary Dendritic Cells NF-κB[41] Macrophage; Dendritic Progenitor RUNX1 [42] Cells Cancer Lung Cancer - H157 Cells Cyclin D1 [43] Cervical Cancer - HeLa Cells Cyclin D2 [44]; E2F1 [44] Breast Cancer - MDA-MB-231 JNK1 [45]; c-Jun [45]; Cyclin D1 [45] Cells CEBPα [46]; myc [46]; c-Jun [18]; JunB [18]; CEBPα c-Jun [18]; JunB [18]; CEBPα [46]; Acute Myeloid Leukemia–Mouse STAT1 [46]; IL-6 [46]; [46]; myc [46]; STAT1 [46]; IL-6 myc [46]; STAT1 [46]; IL-6 [46]; Models ERK1/2 [46]; PKB/AKT [46]; ERK1/2 [46]; PKB/AKT ERK1/2 [46]; PKB/AKT [46] [46] [46] c-Myc [47,48]; Bcl2 [47,48]; Acute Myeloid Myc [48]; Bcl2 [48]; TGF-B [48]; CBFA2T3 [47]; CSF1R [47]; PU.1 Leukemia–Kusami-1 Cells p57 [48] [47]; TGF-B [48]; p57 [48] Cells 2019, 8, 1373 3 of 32 Table 1. Cont. Tissue/Cell Line Nr4a1 Nr4a2 Nr4a3 Endothelium Primary Human Umbilical Vein Cyclin A [49]; Cyclin D1 [49]; PCNA Endothelial Cells [49]; E2F [49] Intestine Intestinal Epithelium - IEC-6 Cells p21Cip1 [50] Uterus TGFβ3 [51]; SMAD3 [51]; TGFβ3 [51]; SMAD3 [51]; TGFβ3 [51]; SMAD3 [51]; collagen Leiomyoma Smooth Muscle Cells collagen genes 1A1, 6A1, collagen genes 1A1, 6A1, 6A2, genes 1A1, 6A1, 6A2, and 16A1 [51] 6A2, and 16A1 [51] and 16A1 [51] 2.1. Liver Liver tissue has a remarkable ability to regenerate. Controlled cell proliferation is key in this process to regenerate tissue without becoming malignant. Hepatic stellate cell proliferation has also been identified as an issue in liver fibrosis. In both situations the Nr4a subfamily is a regulatory factor. 2.1.1. Anti-Proliferation When subjected to partial hepatectomy Nr4a1 deficient mice generated by homologous recombination showed increase in NF-κB and STAT3 protein levels which in turn induced Cyclin B1, Cyclin D1, Cyclin E1, Cdk4 and Cdk2 expression within 24 h, demonstrating that Nr4a1 limits regeneration in hepatocytes [26]. It is important to note, however, that recent findings have shown that the Nr4a1 knock out mouse used in this study (and others) expresses the N-terminal domain of Nr4a1 and that this is sufficient to bind and stabilize HIF1α [52]. While no change in hepatocyte proliferation was demonstrated in this study, it does emphasize the need to validate these results in the floxed Nr4a1 model. In the hepatic stellate cell HSC-T6 cell line Nr4a2 inhibition by siRNA led to increased cell proliferation and decreased phosphorylation of the MAPK pathway members ERK1/2, p38 and JNK [28]. This result was supported by a marked increase in ERK1/2 and p38 phosphorylation observed in HSC-T6 cells overexpressing Nr4a2, along with decreased proliferation [29]. 2.1.2. Pro-Proliferation While Nr4a1 and Nr4a2 inhibit proliferation in liver tissues, Nr4a3 promotes proliferation in both hepatocytes and hepatic stellate cells. Mice treated with Nr4a3 shRNA were subjected to partial hepatectomy. Decreased expression of Cyclin D1, Cyclin E1, VCAM1 and PCNA were observed, as well as lower liver weight. Overexpression of Nr4a3 increased expression of these same genes. Chromatin immunoprecipitation (ChIP) revealed that Nr4a3 directly interacts with the Cyclin D1 promoter, demonstrating that it is a direct Nr4a3 target in hepatocytes [27]. In hepatic stellate cells TGF-β1 was sufficient to drive activation and proliferation. TGF-β1 was observed to increase expression of Nr4a3 and Nr4a3 inhibition impaired primary hepatic stellate cell proliferation, demonstrating Nr4a30s role in TGF-β1 mediated hepatic stellate cell activation and proliferation [53]. As observed with hepatocytes, the Nr4a subfamily has opposing roles in controlling proliferation which may assist in balancing healthy benign growth. 2.2. Muscle In smooth and cardiac muscle, proliferation is often associated with hypertrophy and disease pathogenesis such as atherosclerosis, restenosis and heart disease. Again, we see Nr4a’s opposing roles in regulating this process. Cells 2019, 8, 1373 4 of 32 2.2.1. Anti-Proliferation Vascular smooth muscle cells (VSMCs) have been used to study the Nr4a role in smooth muscle. VSMCs derived from pulmonary artery and saphenous vein, PDGF, 5-HT or stress were shown to cause proliferation. When Nr4a1 was overexpressed, it inhibited proliferation by blocking the STAT3/Pim-1/NFAT pathway members which decreased Cyclin D1 and PCNA expression [30–32].
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